1. GLOBAL BIOANALYSIS CONSORTIUM
Regulated Bioanalysis
A Proposed Global Harmonization Process
presented by Peter Van Amsterdam and Rafael Barrientos, for GBC
at 1st Latin American Meeting on Bioanalysis,
May 2012, São Paulo - Brazil

2. 1. Historic perspective on the evolution of
Regulated Bioanalysis (Peter Van
Amsterdam)
2. Recap on GBC goals and structure (Rafael
Barrientos)
3. Harmonization team activities – GBC sessions
Latin America members presentation (Rafael
Barrientos)
Outline
2

3. 1. Historic perspective on the evolution of
Regulated Bioanalysis
3

4. The early years of regulations
 1965: EEC 65/65 (reaction to Thalidomide)
• No real focus on bioanalysis
 1978: 21 CFR 58
 1982: OECD 1
• Both are General GLP guidelines (preclinical safety)
• quality system ensure the uniformity, consistency, reliability, reproducibility, quality,
and integrity pre-clinical safety tests.
 Eighties (flowing over in the Nineties)
• Increased focus on Bioequivalence studies (including paragraphs on bioanalytical
methodology to be applied
• EU, FDA, Australia, Canada to lead
 BMV workshop – (Cristal City-I):
• < 1990 = lack of uniformity in industry wrt validation bioanalytical methods
• Cristal City-I was first international conference with focus on Bioanalytical method
validation and sample analysis
• Resulted in Shah paper (Pharm Res. 1992;9:588-592).
4

5. Bioanalysis regulations >1990: simplified
Crystal City I CP
(Shah Paper)
2001 FDA
Guidance
CC-I CC-II CC-III
Crystal City
Conferences:
Conference
papers (CP):
Regulatory
Guidance:
Additional
white papers:
CC-ISR
CC-ISR CP
Fast
1990 2000 2010
CC III CP
Viswanathan
CC II CP
Shah (chrom.)
Miller (LBA)
DeSilva
5

6. The broader and global context
20201960 1970 1980
1965:
65/65/EEC
1979:
US 58cfr21
1982:
OECD GLP
A B C
A. scientist adopting home designed quality systems
B. scientist shopping for inspiration in other areas – peers, DIN, EPA,..
C. scientist regrouped around Shah paper
D. multiple countries issuing regulations of BA included in BE guidelines
E. Industry increase frequency on coming together (e.g. APA, EBF, CVG)
some issue recommendation papers after (broad) internal discussions
Anvisa RDC 899
HC remove ISR
1988:
Australian draft
CO6: 7581c
EMA draft
Anvisa update
Open letter
to FDA /EMA
GBC
formed
More countries or
regions likely to
issue Guidelines
D
E
1990 2000 2010
Thalidomide
6

7. 1995-2010
A bucket full of other
adjacent regulations:
Cfr 21 part 11
ICH S3A, ICH-E6
ICH M3 (R2)
MHRA GcLP
Etc…
20201960 1970 1980
1965:
65/65/EEC
1979:
US 58cfr21
1982:
OECD GLP
A B C
Anvisa RDC 899
HC remove ISR
1988:
Australian draft
CO6: 7581c
EMA draft
Anvisa update
Open letter
to FDA /EMA
GBC
formed
More countries or
regions likely to
issue Guidelines
D
E
1990
The broader and global
context: more detail
2000 2010
Thalidomide
A. scientist adopting home designed quality systems
B. scientist shopping for inspiration in other areas – peers, DIN, EPA,..
C. scientist regrouped around Shah paper
D. multiple countries issuing regulations of BA included in BE guidelines
E. Industry increase frequency on coming together (e.g. APA, EBF, CVG)
some issue recommendation papers after (broad) internal discussions
7

8. Technology developments
20201960 1970 1980 1990 2000 2010
TLC, GC
(LC-UV)
immunoassays
Sub mcg/mL
GC2, GC-MS
GC-NPD/ECD
HPLC-UV/fl
immunoassays
ng/mL
TLC
Immunoassays
bioassays
mcg/mL
GC2, GC-MS
GC-NPD/ECD
HPLC-UV/fl
LC-MS/MS,
Old school
Immunoassays
Sub ng/mL
LC-MS/MS,
New generation
Binding assays
pg/mL
New generation
LC-MS/MS and
Binding assays,
other?
Sub pg/mL?
8

9. Highlights from technology
Manual low throughput
Mcg limits of quantification
Chromatography: Multiple assay formats
LBA: Limited assay formats
Paper raw data
PK of unchanged drug
 automated high throughput
 sub-pg limits of quantification
 1 single assay format (LC-MS/MS)
 multiple (and novel) assay formats
 electronic raw data
 PK/PD, TK, metabolites, biomarkers,..
20201960 1970 1980 1990 2000 2010
a lot
happened
9

10. Other factors…
Evolutions in the Pharma landscape around the turn of the century and
how it (may have) impacted regulated bioanalysis across industry:
 Portfolio changes in industry: new targets, new disease models
• Increased development time for small molecule scaffold  less NCE
• Increased emphasis on peptides and proteins  more NBE
– Enabling also faster development from Discovery to market
– Creating a boost in (new and innovative) LBA developments
 Patent expirations (of multi-billion selling drugs):
• R&D optimise life cycle management
– More Bioequivalence (BEQ) studies filed from R&D Pharma
• Generic Pharma boosting
– More BEQ studies (with bioanalysis often outsourced) filed from generic Pharma
• Economic pressure on R&D Pharma calling for re-organisations resulting
in more (bioanalytical) outsourcing
• CROs growing their business exponentially (also outside EU/US)
– More people involved = more difference in how quality is achieved and documented
– More regions involved
10

11. Back to Bioanalysis…
11

12. Crystal City I to…………………………………………………………..Crystal City II
patent
expiry
technology
developments
CRO
booming
portfolio
changes
2
0
0
1
FDA
1990
2000
(Re-)united at last, or??
See next slide
On the way from CC-I to
CC-II, a lot of bioanalytical
experience was built
12

13. > 2001……
• Individual interpretations of Guidance  ambiguity
(individual flavors both from industry + HA inspectors (483))
• Technology developments not covered in Guidance
• Added value of new regulatory insights sometimes poorly
understood (ISR, FDC,…)
• Regulatory awareness in an increasing number of regions
leading to multiple interpretations of FDA guidance
• Some regions felt need for own guidelines (EMA, ANVISA)
• More bioanalysis is performed in more areas (metabolites,
tissue, biomarkers, immune response, ..) requires new
guidance
• More bioanalysis preformed outside EU/US, i.e. APAC, LA
urging scientist to re-unite
From the FDA guidance onwards
Ligand Binding community didn’t feel their science
was fully recognized in FDA Guidance
(Findlay-2000, DeSilva-2003)
Industry
united around
one Guidance
2001
2010
Increasing number of bioanalysis meetings in all
regions, sparking peer discussions
Open letter to the Health Authorities from
EBF, AAPS, CVG and APA (Bioanalysis, 2010)
13

14. 14

15. 2010
OR
2001
> 2012
Can GBC re-unite towards a harmonized understanding and
application of bioanalysis guidelines and convince the world?
15

16. … or will we all be playing the game differently?

17. Cooperation, team work, building bridges toward a global
harmonization in Bioanalysis
17

18. 2. Recap on GBC goals and structure
18

19. Mission Statement
Create an all inclusive Global Bioanalysis
Consortium (GBC) consisting of represented
scientific associations with world wide influence
to merge existing or emerging bioanalytical
guidance to create one, unified consensus
document that can be presented to the regulatory
bodies/health authorities in various countries.
19

20. GBC: Goals and Objectives
• To bring together stakeholders from the pharmaceutical
industry, contract research organizations and academia
to share current understanding of bioanalysis
guidelines, identify differences in these guidelines or
differences in the interpretation or application thereof to
routine regulated bioanalysis.
• To come forward with recommendations to Health
Authorities and regulatory bodies worldwide on globally
agreed best practices for Bioanalytical Method Validation
(BMV) and application of such methods/technologies to
the analysis of drugs of all molecular sizes in support of
clinical and nonclinical studies.
20

21. • To invite relevant stakeholders, from industry, academia,
Health Authorities and regulatory bodies, to jointly
discuss the GBC recommendations at a global
conference(s) in order to achieve globally agreed
guidelines on bioanalysis.
• Going forward, to serve as a pivot point on the
continued harmonized interpretation and/or updates of
globally agreed guidelines.
GBC: Goals and Objectives
21

22. Organization Chart
Harmonization
Team # 1
Harmonization
Team # 2
Harmonization
Team # ‘n’
Steering Committee (GBC-SC)
Scientific Leadership Team (GBC-SLT)
22

23. North America (US + Canada)
• Mark Arnold (AAPS)
• Binodh DeSilva (AAPS)
• Fabio Garofolo (CFABS)
Latin America (South America + Mexico)
• Rafael Barrientos (Acbio)
Asia Pacific (Asia + Pacific area)
• Shinobu Kudoh (JBF)
• Shrinivas Savale (APA-India)
• Daniel Tang (SBDG&BBDG)
Europe (Europe + Africa/Middle East)
• Peter van Amsterdam (EBF)
• Michaela Golob (EBF)
• Philip Timmerman (EBF)
23
Steering Committee Members
P.Timmerman D. Tang, S. Kudoh, P. van Amsterdam, S. Savale, M. Golob. F. Garofolo, B. DeSilva, R. Barrientos, M. Arnold,
Live Live
EBF: European Bioanalysis Forum
AAPS: American Association of Pharmaceutical Scientists
CFABS Canadian Forum for Analytical and Bioanalytical Sciences
ACBio: Assosiacao BRASILEIRA DOS CENTROS DE BIODISPONIBILIDADE E BIOEQUIVALENCIA
BBDS/SBDS:Beijing Bioanalytical Discussion Group/Shanghai Bioanalytical Discussion Group

24. Active Harmonization Teams
All
Topics Common
to all molecules
A
A1
Scope and regulations
A2
Tiered approaches
for method validation
A3
Method Transfer,
partial/cross validations
A4
Reference standards
and reagents
A5
Sample Management
A6
Stability
A7
Repeat analysis
and ISR
A8
Documentation
A9
Analytical Instrument
Qualification
A10
New Frontiers
A11
Biomarkers
Large Molecule
L
L1
Large molecule
specific run acceptance
L2
Large molecule
specific assay operation
L3
Assay formats
L4
Reagents and
their Stability
L5
Automation practices
in LM bioanalysis
L6
Immunogenicity
effect on Pk
Small Molecule
(Chromatographic
Assays)
S
S1
Small molecule
specific run acceptance
S2
Small molecule
specific assay operation
S3
Chromatographic
Run Quality Assessment
24

25. Team Leaders SC Sponsor Team Leaders SC Sponsor
A1:
A2:
A4:
A6:
A11:
Surendra Bansal
Steve Lowes
Joseph Bower
Nico van den Merbel
Russ Weiner
Philip Timmerman
EBF, Europe
Daniel Tang BBDS &
SBDS , Asia Pacific
Shinobu Kudoh
JBF, Asia Pacific
L1:
L2:
L3:
L4:
L5:
L6:
Marian Kelley
Lauren Stevenson
Sherri Dudal
Lindsay King
Scott Davis
Jeff Sailstad
Michaela Golob
EBF , Europe
Fabio Garofolo
CVG, N America
Binodh DeSilva
AAPS , N America
A3:
A5:
A7:
A8:
Ray Briggs
Mike Redrup
Eric Fluhler
Tom Verhaeghe
Peter van Amsterdam
EBF , Europe
Shrinivas Savale
APA-India, Asia Pacific
A9: Chad Briscoe
A10: Bob Bethem/
Chad Ray
S1: Douglas Fast
S2: Eric Woolf
S3: Stuart McDougall
Rafael Barrientos
ACBio, L America
Mark Arnold
AAPS , N America
SC Sponsorship of Harmonization Teams

26. Latin America, 11
A1 Myriam Salvadori A11 -
A2 Vinicius Resende L1 -
A3 Paulo Galvinas L2 Mario Dominguez
A4 Katia Pastre L3 -
A5 Thales Cardoso L4 -
A6 M. Francesca
Riccio
L5 -
A7 Vinícius Resende L6 -
A8 Myriam Salvadori S1 Maristela Andraus
and Gabriel
Marcelín
A9 Katia Pastre S2 Miguel Vago and
Gabriel Marcelín
A10 - S3 M. Francesca Ricio
APAC China, 7
A1 1 A11 -
A2 - L1 1
A3 1 L2 -
A4 - L3 -
A5 - L4 -
A6 1 L5 -
A7 1 L6 -
A8 - S1 -
A9 1 S2 -
A10 - S3 1
APAC India, 21
A1 1 A11 -
A2 1 L1 2
A3 1 L2 1
A4 - L3 1
A5 1 L4 -
A6 1 L5 -
A7 2 L6 1
A8 1 S1 1
A9 1 S2 3
A10 1 S3 2
APAC, 20
A1 1 A11 1
A2 1 L1 1
A3 1 L2 1
A4 1 L3 1
A5 1 L4 1
A6 1 L5 1
A7 1 L6 1
A8 1 S1 1
A9 1 S2 1
A10 1 S3 1
Europe, 55
A1 1 A11 3
A2 3 L1 3
A3 3 L2 2
A4 2 L3 4
A5 3 L4 2
A6 3 L5 2
A7 3 L6 1
A8 3 S1 3
A9 2 S2 2
A10 7 S3 3
N. America, 87
A1 4 A11 4
A2 5 L1 4
A3 3 L2 4
A4 2 L3 5
A5 3 L4 6
A6 3 L5 5
A7 4 L6 11
A8 3 S1 5
A9 4 S2 3
A10 5 S3 4

27. HT Leaders Objectives
• Remove concepts of company or region from your thinking - you’re leading
a global effort.
• Facilitate discussion, don’t push your personal agenda
Teams are to develop science-based best practices
• Recognize that consensus may not be possible. People with different
views will spark vigorous discussion.
• Prevent bullying by the loudest voice. Allow and stimulate less extrovert
people to share their opinion and experience
• Recognize that some governments /regions may have regulations that are
outdated or inconsistent with a science-based approach. Be prepared to
defend proposals that conflict with existing regulations.
80:20 Rule
• Not all items within the Scope of the Team need to be redone, in fact 80%
may already have industry-regulatory consensus
Harmonization Team Objectives
27

28. HT activities
Compile regional information on regulations
and practices related to the Team’s scope
• Share regulations with other Team
• A lot of prework has been done
Evaluate scope list to categorize those that:
• Are fully agreed to
• Are generally agreed to
• Have no agreement
28

29. HT activities
• For those that are agreed to write science-based language as proposed
position
• For those that are generally agreed to, discuss differences and develop
science-based position, write science-based language as proposed position
• For those that are not generally agreed to, prioritize the list to enable
discussion on those with the greatest impact to the bioanalytical community
• Have internal team discussions and where possible, develop recommendations
• Where no consensus is achieved, provide arguments on both sides
• Utilize GBC SC and other HT leaders for input
Team members should reach back to regional organizations for input
• Query regional organization membership on positions on a topic(s)
• Coordinate across Teams. Regional memberships will lose interest if frequently
bombarded with requests.
29

30. HT activities
Proposals and outcome
• Write proposals in a clear and concise manner that are suitable for
publication, include references to existing literature and regulations
• As noted above, where proposal conflicts with existing regulations,
additional details and discussion may be needed
• Create slide deck for communication of proposals that go into greater
depth and may contain data. This will be foundation of
• Presentations at regional meetings
• Presentation at international meeting
• Publications in international journals
• Note: timing of publications in relation to the Global Meeting
• Where no consensus is achieved, provide arguments on both sides
30

31. New insights developed at GBC-SC meetings
Feedback indicates a desire for increased engagement, input
and contribution from the different regions
 The current team dynamics and composition may not sufficiently
engage the broader scientific community
 Open discussion
Desire to provide opportunity for regular updates on GBC
progress in an open format
 The current process may lead to a significant period of ‘radio silence’
 Prevent all GBC-proposals coming as one avalanche at the global
meeting, which may be too much to manage if not previewed
 Provide regulators a chance to get better understanding of activities of
GBC

32. Potential win-win
• Connect GBC better with the regions
 Reconnection with supporting organizations as our day to day supporters
 All regions get expanded opportunity to be involved
• Engage and inform a broader scientific community in
advance of the global meeting
 Allow BA community to comment within the comfort zone of their region
 Allow BA community to comment to their regional organizations
• Provide the opportunity to publish a summary of thinking in
advance of the global meeting
 Allow global community of practice to know what’s coming
 Be more engaged in the global meeting and not be caught by surprise
• Create visibility, recognition and connectivity in regions
 for HT-L and HT members
 for SC members
• Create flexibility to present on topics in need of influencing
current thinking of regulators or on emerging guidelines

33. LA representative activities within GBC
• TCs:
– SC only meetings (every 2 weeks)
– HTLs meetings (as needed)
– Sponsored HTLs (every 3rd Monday of each month)
– LA HT members: as needed
• Face-to-face meetings:
– SC only: Barcelona/Spain – Nov. 11
– SC + HTLs: San Antonio/USA – Mar. 12
• Reporting news:
– Every meeting @ Acbio bioanalysis focus group
– Acbio´s Board meetings
– Emails throughout the RLABB (Rede Latinoamericana de
Bioequivalência)
– Meetings with Cobio/Anvisa

34. Original planning
• HT-L/SC face to face in San Antonio
• Continue FB at regional meetings across all regions
• Load HT draft recommendation slides on GBC website in June
• GBC meeting in Noordwijk, the Netherlands 25-27 September
• Publish final recommendation slides on the website in October
New planning
• HT-L/SC face to face in San Antonio (done)
• Load progress slides on GBC website from April onwards (new)
• Continue feedback and dialogue with broader scientific community at regional meetings
across all regions (intensify)
• Load HT draft recommendation slides on GBC website in June
• GBC meeting in Noordwijk, the Netherlands 25-27 Sept. (relocated – see next bullet)
• GBC meeting moved to Washington DC area, 2 days prior to CC-V (new)
• Publish final recommendation slides on the website in October (postpone until clarity
on dates of GBC meeting)
How to move forward?

35. What triggered this change?
• FDA plan/communication to release draft of updated
guidance in summer. As follow up, AAPS/FDA will organize a
Cristal City V (CC-V) meeting in Washington DC area within 90
days of draft guidance release
• Consequence for GBC meeting:
– CC-V and GBC meeting involve the same audience separated
potentially by only few weeks or months
– Travel restrictions in industry will limit delegates to travel to two
similar meetings in 2 different regions
– Attendance to CC-V may be prioritized by industry over GBC meeting
– By connecting the GBC meeting in time and place, GBC and delegates
can participate in both meetings;
• Provide consolidated feedback to and get input from the Global
Community on draft recomendations (=original intenten of GBC meeting)
• At the CC-V meeting, share this consolidated GBC as input into FDA draft
Guidance (=impact as per GBC Mision and Vision)

36. Additional reflections
• GBC needs to ensure their global mission is not
redirected to only providing input on draft FDA
guidance but maintains it global perspective
– Scope and agenda of GBC remains unchanged
– Upon release of the draft FDA guidance, Harmonization
Teams (not L) needs to ensure that the scope and content
of the team discussions does not change relative to FDA
guidance
• Nevertheless, major discussion points can be identified in
preparation for discussion @CC-V
– By intensifying the feedback from other regional meetings
and earlier publication of our draft recommendation slides
on the GBC website from April onwards, scientist in all
regions should feel invited to also intensify their input.

37. Updated Proposed way forward
HT- L identification
2011
Start up phase
2012
HT identification
HT working on content
working close with SLT
Identified regional meetings
• Invite 4-5 topics to present the progress of their teams and to share.
• Present high level progress on other topics and Get input
SLT f-2-f
Consolidation
and joint
discussion of
all topics in
preparation of
Global
Meeting
Global Meeting
2-day
Conference in
Washington DC
(USA), 2 days
before Crystal
City V

38. Other regional meetings
SLT f-2-f
Consolidation
and joint
discussion of
all topics in
preparation of
Global
Meeting
Global Meeting
2-day
Conference in
Washington DC
(USA), 2 days
before Crystal
City V
Updated Proposed way forward
Zoom in

39. Proposed way forward - details
Global
Meeting
‘Recommendation
Slides’
on GBC website for
all to read, in
preparation of
Global Meeting
March e.o. June
max. 90 days
post release
of FDA draft
Guidance.
Current
exact date
unknown
2012
HT-L/SC F2F
San Antonio (Tx)
Consolidation and
joint discussion of
all topics in
preparation of
Global Meeting
Crystal City V
April
draft slides
Consolidatio
n of slides
from all HTs
from SA (Tx)
on GBC
website
Intensify consolidation
and consultation from
teams and from regional
meetings, building on
slides presented at HT-L
in San Antonio
APAC
CPSA
e.o.
April
LA
ACBio
mid
May
EU
EBF
mid
June
APAC
JBF
mid
Aug.
2 days prior
to CC-V
NA
NBC
mid
May
US
LoL
e.o.
July
Continued slide iterations, based on HT team
meetings and input form the regions